1. Field of the Invention
The invention is directed to novel crystalline solvates of paclitaxel with organic solvents, which are useful as sources of paclitaxel for therapeutic treatments. The inventive concept further includes methods of forming such solvates from paclitaxel-containing materials, and methods of obtaining paclitaxel from these solvates.
2. Description of Related Art
Paclitaxel, a diterpene taxane compound with significant antineoplastic properties having the structure: is a natural product first extracted from the bark of the Pacific yew tree, Taxus brevifolia. It is commercially available as Taxol®, Bristol-Myers Squibb Co. Taxol® has been shown to have excellent antitumor activity in in vivo animal models, and recent studies have elucidated its unique mode of action, which involves abnormal polymerization of tubulin and disruption of mitosis during the cell cycle. Taxol® has been approved for the treatment of refractory advanced ovarian cancer, breast cancer, non-small cell lung cancer and AIDS-related Kaposi's Sarcoma.
The results of paclitaxel clinical studies are reported in scientific periodicals and have been reviewed by numerous authors, such as Rowinsky et al., Pharmac. Ther., 52, 35-84 (1991); Spencer et al., Drugs, 48 (5), 794-847 (1994); K. C. Nicolau et al., Angew. Chem., Int. Ed. Eng., 33, 15-44 (1994); F. A. Holmes et al., “Taxane Anticancer Agents—Basic Science and Current Status”, edited by Gunda I. Georg et al., 31-57 American Chemical Society, Washington, D.C. (1995); S. G. Arbuck et al., “Taxol® Science and Applications”, edited by Matthew Suffness, 379-416, CRC Press, Boca Raton, Fla. (1995), and the references cited therein.
The patent literature describes many methods of isolating paclitaxel from plant sources, many of which involve extraction with various organic solvent systems followed by chromatographic separation.
The procedures described in U.S. Pat. Nos. 5,380,916, 5,475,120, and 5,670,673 to Rao (also PCT Publication No. WO 92/07842), for example, use a series of solvent extractions employing ethanol, chloroform, ligroin, benzene and methanol followed by reverse phase chromatography using a HPLC column with an acetonitrile eluent.
The procedures described in U.S. Pat. Nos. 5,279,949 and 5,478,736 to Nair (also PCT Publication No. WO 97/09443) use activated charcoal for decolorizing an initial 70% ethanol/water extract and early filtration through Celite® (diatomaceous earth). The decolorized extract is subsequently extracted with ethyl acetate, and evaporated to precipitate taxanes. The taxanes are re-dissolved in ethyl acetate and loaded onto a first silica column that is eluted with a hexane/ethyl acetate gradient, and further purified by tandem silica columns or, alternatively, by reverse phase chromatography.
U.S. Pat. No. 6,136,989 discloses a method of making an acetone mixture containing paclitaxel which includes extracting a paclitaxel-containing material with methanol to obtain a methanol extract; partitioning the methanol extract by liquid-liquid extraction with methylene chloride and water to form a two phase system having a methanolic phase containing methanol/water and a methylene chloride phase containing methylene chloride and paclitaxel; removing methanol and water from the methylene chloride phase to obtain a concentrated extract containing paclitaxel; contacting the concentrated extract with a silica matrix then eluting the silica matrix to obtain an eluate containing at least 5% (w/w) paclitaxel and adding acetone to the eluate to obtain an acetone mixture. According to the patent, acetone/water precipitation of an acetone mixture containing at least 5% paclitaxel will provide a precipitate containing at least 20% paclitaxel, and an acetone/water precipitation of an acetone mixture containing at least 10% paclitaxel will provide a precipitate containing 40% to 50% paclitaxel.
While the above patents are directed to the isolation of paclitaxel, none of them describes the crystallization of a novel, previously unknown paclitaxel solvate from a solution of paclitaxel and one or more organic solvents.
Paclitaxel has been used with organic solvents in the prior art in the development of pharmaceutical formulations. Paclitaxel is known to be poorly soluble in water, which limits the available formulations for administering paclitaxel to a patient. The formulation usually used contains 50% (v/v) alcohol and an 88-fold excess of polyoxyethylated castor oil (Cremophor® EL).
Various efforts have been made to discover other media for administration of paclitaxel to a patient. For example, U.S. Pat. No. 5,877,205 describes paclitaxel dissolved in a first organic solvent (e.g. N,N′-dimethylacetamide or dimethylsulfoxide), followed by a secondary solvent, such as polyethyleneglycol 400, for final dilution in an aqueous solvent.
U.S. Pat. No. 6,017,948 discloses paclitaxel formulations asserted to be suitable for administration to a patient comprising a solution of paclitaxel in water-miscible, non-aqueous solvents, such as N-methyl pyrrolidone, propylene glycol, ethyl acetate, dimethyl sulfoxide, N,N′-dimethylacetamide, benzyl alcohol, 2-pyrrolidone, or benzyl benzoate.
Both the above-mentioned patents are directed to liquid formulations for administration by infusion. None of the above patents discloses the crystallization of paclitaxel solvates from their respective formulations.